Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer proliferation and survival.

There are limited therapeutic options for patients with advanced prostate cancer (PCa). We previously found that heat shock factor 1 (HSF1) expression is increased in PCa and is an actionable target. In this manuscript, we identify that HSF1 regulates the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystathionine-ß-synthase (CBS). We find that HSF1 directly binds the CBS gene and upregulates CBS mRNA levels. Targeting CBS decreases PCa growth and induces tumor cell death while benign prostate cells are largely unaffected. Combined inhibition of HSF1 and CBS results in more pronounced inhibition of PCa cell proliferation and reduction of transsulfuration pathway metabolites. Combination of HSF1 and CBS knockout decreases tumor size for a small cell PCa xenograft mouse model. Our study thus provides new insights into the molecular mechanism of HSF1 function and an effective therapeutic strategy against advanced PCa.

Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.

BACKGROUND: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear. METHODS: Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, NCI-H660) were treated with DRP-104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP-104 on glutamine pathways. Efficacy of DRP-104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI-H660. RESULTS: DRP-104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP-104 treated CRPC cells were rescued by the addition of nucleosides. DRP-104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity. CONCLUSIONS: The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.

On-field physical activity of Special Olympics athletes and Unified Partners during the 2022 Special Olympics World Unified Cup.

BACKGROUND: Special Olympics is a sport organisation spearheading efforts to increase physical activity accessibility through inclusive sport. The Unified Sports® initiative brings together Special Olympics athletes (with intellectual disabilities) and Unified partners (without a disability) in sport training and competition on the same team. The study aims to objectively evaluate differences in on-field physical activity levels between athletes and partners during the 2022 Special Olympics World Unified Cup, an international soccer (i.e., football) competition. Participants were Special Olympics athletes (n = 96; 44 females, 52 males) and Unified partners (n = 70; 34 females and 36 males) competing in the women's and men's tournaments. METHODS: On-field actigraph accelerometry measured physical activity from 166 players, over 29 matches, and totalling 493 player-matches. RESULTS: In the women's tournament, nearly identical estimates of moderate-to-vigorous physical activity levels (MVPA) were observed between athletes and partners (P = .409). However, a significant group difference was observed within a specific physical activity intensity category as partners accrued more minutes of very vigorous physical activity than athletes (P < .001). In the men's tournament, no significant differences were also observed between athletes and partners for minutes of MVPA (P = .341), but athletes engaged in significantly more vigorous physical activity (P < .001), and partners had more minutes of very vigorous physical activity (P < .001). CONCLUSIONS: The results suggest that on-field physical activity levels were similar between players with and without intellectual disabilities during Unified Sports competition.

Climate-driven variability of the Southern Ocean CO2 sink.

The Southern Ocean is a major sink of atmospheric CO2, but the nature and magnitude of its variability remains uncertain and debated. Estimates based on observations suggest substantial variability that is not reproduced by process-based ocean models, with increasingly divergent estimates over the past decade. We examine potential constraints on the nature and magnitude of climate-driven variability of the Southern Ocean CO2 sink from observation-based air-sea O2 fluxes. On interannual time scales, the variability in the air-sea fluxes of CO2 and O2 estimated from observations is consistent across the two species and positively correlated with the variability simulated by ocean models. Our analysis suggests that variations in ocean ventilation related to the Southern Annular Mode are responsible for this interannual variability. On decadal time scales, the existence of significant variability in the air-sea CO2 flux estimated from observations also tends to be supported by observation-based estimates of O2 flux variability. However, the large decadal variability in air-sea CO2 flux is absent from ocean models. Our analysis suggests that issues in representing the balance between the thermal and non-thermal components of the CO2 sink and/or insufficient variability in mode water formation might contribute to the lack of decadal variability in the current generation of ocean models. This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.

Rewiring of the N-Glycome with prostate cancer progression and therapy resistance.

An understanding of the molecular features associated with prostate cancer progression (PCa) and resistance to hormonal therapy is crucial for the identification of new targets that can be utilized to treat advanced disease and prolong patient survival. The glycome, which encompasses all sugar polymers (glycans) synthesized by cells, has remained relatively unexplored in the context of advanced PCa despite the fact that glycans have great potential value as biomarkers and therapeutic targets due to their high density on the cell surface. Using imaging mass spectrometry (IMS), we profiled the N-linked glycans in tumor tissue derived from 131 patients representing the major disease states of PCa to identify glycosylation changes associated with loss of tumor cell differentiation, disease remission, therapy resistance and disease recurrence, as well as neuroendocrine (NE) differentiation which is a major mechanism for therapy failure. Our results indicate significant changes to the glycosylation patterns in various stages of PCa, notably a decrease in tri- and tetraantennary glycans correlating with disease remission, a subsequent increase in these structures with the transition to therapy-resistant PCa, and downregulation of complex N-glycans correlating with NE differentiation. Furthermore, both nonglucosylated and monoglucosylated mannose 9 demonstrate aberrant upregulation in therapy-resistant PCa which may be useful therapeutic targets as these structures are not normally presented in healthy tissue. Our findings characterize changes to the tumor glycome that occur with hormonal therapy and the development of castration-resistant PCa (CRPC), identifying several glycan markers and signatures which may be useful for diagnostic or therapeutic purposes.

Oncofetal protein glypican-3 is a biomarker and critical regulator of function for neuroendocrine cells in prostate cancer.

Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression. © 2023 The Pathological Society of Great Britain and Ireland.

Novel directions of precision oncology: circulating microbial DNA emerging in cancer-microbiome areas.

Microbiome research has extended into the cancer area in the past decades. Microbes can affect oncogenesis, progression, and treatment response through various mechanisms, including direct regulation and indirect impacts. Microbiota-associated detection methods and agents have been developed to facilitate cancer diagnosis and therapy. Additionally, the cancer microbiome has recently been redefined. The identification of intra-tumoral microbes and cancer-related circulating microbial DNA (cmDNA) has promoted novel research in the cancer-microbiome area. In this review, we define the human system of commensal microbes and the cancer microbiome from a brand-new perspective and emphasize the potential value of cmDNA as a promising biomarker in cancer liquid biopsy. We outline all existing studies on the relationship between cmDNA and cancer and the outlook for potential preclinical and clinical applications of cmDNA in cancer precision medicine, as well as critical problems to be overcome in this burgeoning field.

Targeting glutamine metabolism network for the treatment of therapy-resistant prostate cancer.

Advanced and aggressive prostate cancer (PCa) depends on glutamine for survival and proliferation. We have previously shown that inhibition of glutaminase 1, which catalyzes the rate-limiting step of glutamine catabolism, achieves significant therapeutic effect; however, therapy resistance is inevitable. Here we report that while the glutamine carbon is critical to PCa survival, a parallel pathway of glutamine nitrogen catabolism that actively contributes to pyrimidine assembly is equally important for PCa cells. Importantly, we demonstrate a reciprocal feedback mechanism between glutamine carbon and nitrogen pathways which leads to therapy resistance when one of the two pathways is inhibited. Combination treatment to inhibit both pathways simultaneously yields better clinical outcome for advanced PCa patients.

Myeloid mineralocorticoid receptors contribute to skeletal muscle repair in muscular dystrophy and acute muscle injury.

Suppressing mineralocorticoid receptor (MR) activity with MR antagonists is therapeutic for chronic skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. Although mechanisms underlying clinical MR antagonist efficacy for DMD cardiomyopathy and other cardiac diseases are defined, mechanisms in skeletal muscles are not fully elucidated. Myofiber MR knockout improves skeletal muscle force and a subset of dystrophic pathology. However, MR signaling in myeloid cells is known to be a major contributor to cardiac efficacy. To define contributions of myeloid MR in skeletal muscle function and disease, we performed parallel assessments of muscle pathology, cytokine levels, and myeloid cell populations resulting from myeloid MR genetic knockout in muscular dystrophy and acute muscle injury. Myeloid MR knockout led to lower levels of C-C motif chemokine receptor 2 (CCR2)-expressing macrophages, resulting in sustained myofiber damage after acute injury of normal muscle. In acute injury, myeloid MR knockout also led to increased local muscle levels of the enzyme that produces the endogenous MR agonist aldosterone, further supporting important contributions of MR signaling in normal muscle repair. In muscular dystrophy, myeloid MR knockout altered cytokine levels differentially between quadriceps and diaphragm muscles, which contain different myeloid populations. Myeloid MR knockout led to higher levels of fibrosis in dystrophic diaphragm. These results support important contributions of myeloid MR signaling to skeletal muscle repair in acute and chronic injuries and highlight the useful information gained from cell-specific genetic knockouts to delineate mechanisms of pharmacological efficacy.

Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.

Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The HSF1 gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates degradation of nuclear HSF1. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, it potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including an NEPC model, where it caused profound tumor regression. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path for the development of a small-molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers.

Mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy.

AIMS: Duchenne muscular dystrophy (DMD) is an X-linked inherited disease due to dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected patients lose ambulation by age 12 and usually die in the second to third decades of life from cardiac and respiratory failure. Symptomatic treatment includes the use of anti-inflammatory corticosteroids, which are associated with side effects including weight gain, osteoporosis, and increased risk of cardiovascular disease. Novel treatment options include blockade of the renin-angiotensin-aldosterone system, because angiotensin as well as aldosterone contribute to persistent inflammation and fibrosis, and aldosterone blockade represents an efficacious anti-fibrotic approach in cardiac failure. Recent preclinical findings enabled successful clinical testing of a combination of steroidal mineralocorticoid receptor antagonists (MRAs) and angiotensin converting enzyme inhibitors in DMD boys. The efficacy of MRAs alone on dystrophic skeletal muscle and heart has not been investigated. Here, we tested efficacy of the novel non-steroidal MRA finerenone as a monotherapy in a preclinical DMD model. METHODS AND RESULTS: The dystrophin-deficient, utrophin haploinsufficient mouse model of DMD was treated with finerenone and compared with untreated dystrophic and wild-type controls. Grip strength, electrocardiography, cardiac magnetic resonance imaging, muscle force measurements, histological quantification, and gene expression studies were performed. Finerenone treatment alone resulted in significant improvements in clinically relevant functional parameters in both skeletal muscle and heart. Normalized grip strength in rested dystrophic mice treated with finerenone (40.3 ± 1.0 mN/g) was significantly higher (P = 0.0182) compared with untreated dystrophic mice (35.2 ± 1.5 mN/g). Fatigued finerenone-treated dystrophic mice showed an even greater relative improvement (P = 0.0003) in normalized grip strength (37.5 ± 1.1 mN/g) compared with untreated mice (29.7 ± 1.1 mN/g). Finerenone treatment also led to significantly lower (P = 0.0075) susceptibility to limb muscle damage characteristic of DMD measured during a contraction-induced injury protocol. Normalized limb muscle force after five lengthening contractions resulted in retention of 71 ± 7% of baseline force in finerenone-treated compared with only 51 ± 4% in untreated dystrophic mice. Finerenone treatment also prevented significant reductions in myocardial strain rate (P = 0.0409), the earliest sign of DMD cardiomyopathy. Moreover, treatment with finerenone led to very specific cardiac gene expression changes in clock genes that might modify cardiac pathophysiology in this DMD model. CONCLUSIONS: Finerenone administered as a monotherapy is disease modifying for both skeletal muscle and heart in a preclinical DMD model. These findings support further evaluation of finerenone in DMD clinical trials.

Infant blood lipids: a systematic review of predictive value and influential factors.

INTRODUCTION: Blood lipid screening recommendations begin at ages 9-11 years, despite poor adherence and evidence of fatty streaks in coronary arteries by 3 years of age. For cardiovascular disease (CVD) prevention, there may be value in earlier measurement of blood lipids. AREAS COVERED: The present systematic review examines evidence concerning total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides during the infant period. Included are studies examining the extent to which infant blood lipids predict later values in childhood and factors that influence their magnitude. A total of 38 articles (published from 1965 to 2013) met inclusion criteria and were examined in this review. EXPERT OPINION: Longitudinal data suggest correlative relationships in all lipid values around 6 months of age, except for TRG. Influential factors related to blood lipids in infancy include sex, race, family history, feeding, gestational length, birth weight, and maternal factors. Clinical measurement of infant lipids could perhaps provide an early marker of CVD and a target of early CVD prevention strategies. The identification of personal characteristics that associate with high or low values in each lipid could become important in the early identification of vulnerable populations and the promotion of personalized CVD prevention.

Mineralocorticoid Receptor Signaling Contributes to Normal Muscle Repair After Acute Injury.

Acute skeletal muscle injury is followed by a temporal response of immune cells, fibroblasts, and muscle progenitor cells within the muscle microenvironment to restore function. These same cell types are repeatedly activated in muscular dystrophy from chronic muscle injury, but eventually, the regenerative portion of the cycle is disrupted and fibrosis replaces degenerated muscle fibers. Mineralocorticoid receptor (MR) antagonist drugs have been demonstrated to increase skeletal muscle function, decrease fibrosis, and directly improve membrane integrity in muscular dystrophy mice, and therefore are being tested clinically. Conditional knockout of MR from muscle fibers in muscular dystrophy mice also improves skeletal muscle function and decreases fibrosis. The mechanism of efficacy likely results from blocking MR signaling by its endogenous agonist aldosterone, being produced at high local levels in regions of muscle damage by infiltrating myeloid cells. Since chronic and acute injuries share the same cellular processes to regenerate muscle, and MR antagonists are clinically used for a wide variety of conditions, it is crucial to define the role of MR signaling in normal muscle repair after injury. In this study, we performed acute injuries using barium chloride injections into tibialis anterior muscles both in myofiber MR conditional knockout mice on a wild-type background (MRcko) and in MR antagonist-treated wild-type mice. Steps of the muscle regeneration response were analyzed at 1, 4, 7, or 14 days after injury. Presence of the aldosterone synthase enzyme was also assessed during the injury repair process. We show for the first time aldosterone synthase localization in infiltrating immune cells of normal skeletal muscle after acute injury. MRcko mice had an increased muscle area infiltrated by aldosterone synthase positive myeloid cells compared to control injured animals. Both MRcko and MR antagonist treatment stabilized damaged myofibers and increased collagen infiltration or compaction at 4 days post-injury. MR antagonist treatment also led to reduced myofiber size at 7 and 14 days post-injury. These data support that MR signaling contributes to the normal muscle repair process following acute injury. MR antagonist treatment delays muscle fiber growth, so temporary discontinuation of these drugs after a severe muscle injury could be considered.

Mineralocorticoid receptor antagonists improve membrane integrity independent of muscle force in muscular dystrophy.

Mineralocorticoid receptor (MR) drugs have been used clinically for decades to treat cardiovascular diseases. MR antagonists not only show preclinical efficacy for heart in Duchenne muscular dystrophy (DMD) models but also improve skeletal muscle force and muscle membrane integrity. The mechanisms of action of MR antagonists in skeletal muscles are entirely unknown. Since MR are present in many cell types in the muscle microenvironment, it is critical to define cell-intrinsic functions in each cell type to ultimately optimize antagonist efficacy for use in the widest variety of diseases. We generated a new conditional knockout of MR in myofibers and quantified cell-intrinsic mechanistic effects on functional and histological parameters in a DMD mouse model. Skeletal muscle MR deficiency led to improved respiratory muscle force generation and less deleterious fibrosis but did not reproduce MR antagonist efficacy on membrane susceptibility to induced damage. Surprisingly, acute application of MR antagonist to muscles led to improvements in membrane integrity after injury independent of myofiber MR. These data demonstrate that MR antagonists are efficacious to dystrophic skeletal muscles through both myofiber intrinsic effects on muscle force and downstream fibrosis and extrinsic functions on membrane stability. MR antagonists may therefore be applicable for treating more general muscle weakness and possibly other conditions that result from cell injuries.

Gene expression effects of glucocorticoid and mineralocorticoid receptor agonists and antagonists on normal human skeletal muscle.

Mineralocorticoid and glucocorticoid receptors are closely related steroid hormone receptors that regulate gene expression through many of the same hormone response elements. However, their transcriptional activities and effects in skeletal muscles are largely unknown. We recently identified mineralocorticoid receptors (MR) in skeletal muscles after finding that combined treatment with the angiotensin-converting enzyme inhibitor lisinopril and MR antagonist spironolactone was therapeutic in Duchenne muscular dystrophy mouse models. The glucocorticoid receptor (GR) agonist prednisolone is the current standard-of-care treatment for Duchenne muscular dystrophy because it prolongs ambulation, likely due to its anti-inflammatory effects. However, data on whether glucocorticoids have a beneficial or detrimental direct effect on skeletal muscle are controversial. Here, we begin to define the gene expression profiles in normal differentiated human skeletal muscle myotubes treated with MR and GR agonists and antagonists. The MR agonist aldosterone and GR agonist prednisolone had highly overlapping gene expression profiles, supporting the notion that prednisolone acts as both a GR and MR agonist that may have detrimental effects on skeletal muscles. Co-incubations with aldosterone plus either nonspecific or selective MR antagonists, spironolactone or eplerenone, resulted in similar numbers of gene expression changes, suggesting that both drugs can block MR activation to a similar extent. Eplerenone treatment alone decreased a number of important muscle-specific genes. This information may be used to develop biomarkers to monitor clinical efficacy of MR antagonists or GR agonists in muscular dystrophy, develop a temporally coordinated treatment with both drugs, or identify novel therapeutics with more specific downstream targets.

Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target.

Early treatment with heart failure drugs lisinopril and spironolactone improves skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. The angiotensin converting enzyme inhibitor lisinopril and mineralocorticoid receptor (MR) antagonist spironolactone indirectly and directly target MR. The presence and function of MR in skeletal muscle have not been explored. MR mRNA and protein are present in all tested skeletal muscles from both wild-type mice and DMD mouse models. MR expression is cell autonomous in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with MR agonist (aldosterone; EC50 1.3 nM) or antagonist (spironolactone; IC50 1.6 nM), and 53 gene expression differences were identified. Five differences were conserved in quadriceps muscles from dystrophic mice treated with spironolactone plus lisinopril (IC50 0.1 nM) compared with untreated controls. Genes down-regulated more than 2-fold by MR antagonism included FOS, ANKRD1, and GADD45B, with known roles in skeletal muscle, in addition to NPR3 and SERPINA3, bona fide targets of MR in other tissues. MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases.

Rising atmospheric CO2 leads to large impact of biology on Southern Ocean CO2 uptake via changes of the Revelle factor.

The Southern Ocean is a key region for global carbon uptake and is characterized by a strong seasonality with the annual CO2 uptake being mediated by biological carbon drawdown in summer. Here we show that the contribution of biology to CO2 uptake will become even more important until 2100. This is the case even if biological production remains unaltered and can be explained by the decreasing buffer capacity of the ocean as its carbon content increases. The same amount of biological carbon drawdown leads to a more than twice as large reduction in CO2(aq) concentration and hence to a larger CO2 gradient between ocean and atmosphere that drives the gas exchange. While the winter uptake south of 44°S changes little, the summer uptake increases largely and is responsible for the annual mean response. The combination of decreasing buffer capacity and strong seasonality of biological carbon drawdown introduces a strong and increasing seasonality in the anthropogenic carbon uptake. KEY POINTS: Decrease of buffer capacity leads to stronger summer CO2 uptake in the futureBiology will contribute more to future CO2 uptake in Southern OceanSeasonality affects anthropogenic carbon uptake strongly.

Acute kidney injury after ex vivo lung perfusion (EVLP).

BACKGROUND: Ex vivo lung perfusion (EVLP) identifies viability for marginal organs but complicates and lengthens lung transplantation surgery. Preliminary evidence supports equivalency for EVLP-assisted versus traditional (non-EVLP) procedures regarding graft function, postoperative course, mortality, and survival. However, acute kidney injury (AKI), a common serious complication of lung transplantation, has not been assessed. We tested the hypothesis that EVLP-assisted and non-EVLP lung transplantations are associated with different AKI rates. METHODS: Demographic, procedural, and renal data were gathered for 13 EVLP-viable lung transplantations and a non-EVLP group matched 4:1 for single versus double, pulmonary disease, and age. AKI was defined by AKI Network (AKIN) criteria and peak creatinine rise relative to baseline (Δ%Cr) during the 1st 10 postoperative days. Chi-square was performed for AKIN and 2-tailed t test for %ΔCr. RESULTS: Patient and procedural characteristics were similar between the groups. One non-EVLP patient required postoperative dialysis. AKI rates were also similar, as assessed by both AKIN (EVLP 7/13 (54%) vs non-EVLP 32/52 (62%); P = .61) and %ΔCr (EVLP 91 ± 81% vs non-EVLP 72 ± 62%; P = .63). CONCLUSIONS: We did not observe different AKI rates between EVLP-assisted and traditional lung transplant procedures. Although 1 non-EVLP patient required dialysis, AKI rates were otherwise similar. These findings further support EVLP as a strategy to expand the organ pool and reduce concerns for high-renal risk recipients. The small sample size and retrospective design are limitations. However, our sample size is similar to other reports, and it is the first to analyze AKI after EVLP-assisted lung transplantation. Larger multicenter prospective studies are needed.

Optical peaking enhancement in high-speed ring modulators.

Ring resonator modulators (RRM) combine extreme compactness, low power consumption and wavelength division multiplexing functionality, making them a frontrunner for addressing the scalability requirements of short distance optical links. To extend data rates beyond the classically assumed bandwidth capability, we derive and experimentally verify closed form equations of the electro-optic response and asymmetric side band generation resulting from inherent transient time dynamics and leverage these to significantly improve device performance. An equivalent circuit description with a commonly used peaking amplifier model allows straightforward assessment of the effect on existing communication system architectures. A small signal analytical expression of peaking in the electro-optic response of RRMs is derived and used to extend the electro-optic bandwidth of the device above 40 GHz as well as to open eye diagrams penalized by intersymbol interference at 32, 40 and 44 Gbps. Predicted peaking and asymmetric side band generation are in excellent agreement with experiments.

Seasonally different carbon flux changes in the Southern Ocean in response to the southern annular mode.

Stratospheric ozone depletion and emission of greenhouse gases lead to a trend of the southern annular mode (SAM) toward its high-index polarity. The positive phase of the SAM is characterized by stronger than usual westerly winds that induce changes in the physical carbon transport. Changes in the natural carbon budget of the upper 100 m of the Southern Ocean in response to a positive SAM phase are explored with a coupled ecosystem-general circulation model and regression analysis. Previously overlooked processes that are important for the upper ocean carbon budget during a positive SAM period are identified, namely, export production and downward transport of carbon north of the polar front (PF) as large as the upwelling in the south. The limiting micronutrient iron is brought into the surface layer by upwelling and stimulates phytoplankton growth and export production but only in summer. This leads to a drawdown of carbon and less summertime outgassing (or more uptake) of natural CO2. In winter, biological mechanisms are inactive, and the surface ocean equilibrates with the atmosphere by releasing CO2. In the annual mean, the upper ocean region south of the PF loses more carbon by additional export production than by the release of CO2 into the atmosphere, highlighting the role of the biological carbon pump in response to a positive SAM event.